Carl June, via Getty

Carl June on CRISPR, CAR–T and how the Viet­nam War dropped him in­to med­i­cine

In Au­gust of 2011, Carl June and his team pub­lished a land­mark pa­per show­ing their CAR–T treat­ment had cleared a pa­tient of can­cer. A year-to-the-month lat­er, Jen­nifer Doud­na made an even big­ger splash when she pub­lished the first ma­jor CRISPR pa­per, set­ting off a decade of in­tense re­search and some­times even more in­tense pub­lic de­bate over the ethics of what the gene-edit­ing tool could do.

Last week, June, whose CAR–T work was even­tu­al­ly de­vel­oped by No­var­tis in­to Kym­ri­ah, pub­lished in Sci­ence the first US pa­per show­ing how the two could be brought to­geth­er. It was not on­ly one of the first time sci­en­tists have com­bined the ground­break­ing tools, but the first peer-re­viewed Amer­i­can pa­per show­ing how CRISPR could be used in pa­tients.

June used CRISPR to ed­it the cells of three pa­tients with ad­vanced blood can­cer, delet­ing the tra­di­tion­al T cell re­cep­tor and then eras­ing the PD–1 gene, a move de­signed to “un­leash” the im­mune cells. The ther­a­py didn’t cure the pa­tients, but the cells re­mained in the body for a me­di­an of 9 months, a ma­jor hur­dle for the ther­a­py.

End­points caught up with June about the long road both he and the field took to get here, if the treat­ment will ever scale up, and where CRISPR and oth­er ad­vance­ments can lead it.

The in­ter­view has been con­densed and edit­ed. 

You’ve spo­ken in the past about how you start­ed work­ing in this field in the mid-90s af­ter your wife passed away from can­cer. What were some of those ear­ly ef­forts? How did you start?

Well, I grad­u­at­ed from high school and had a low draft num­ber [for the Viet­nam War] and was go­ing to go to study en­gi­neer­ing at Stan­ford, but I was draft­ed and went in­to the Naval Acad­e­my in 1971, and I did that so I wouldn’t have to go to the rice fields.

The war end­ed in ’73, ’74, so when I grad­u­at­ed in 1975, I was al­lowed to go to med­ical school, and then I had a long term com­mit­ment to the Navy be­cause they paid for the Acadamy and Med­ical school. And I was in­ter­est­ed in re­search and at the time, what the Navy cared about was a small scale nu­clear dis­as­ter like in a sub­ma­rine, and like what hap­pened at Cher­nobyl and Fukushi­ma. So they sent me to the Fred  Hutchin­son Can­cer Cen­ter where I got trained in can­cer, as a med­ical on­col­o­gist. I was go­ing to open a bone mar­row trans­plant cen­ter in Bethes­da be­cause the Navy want­ed one in the event of a nu­clear cat­a­stro­phe.

And then in 1989, the Berlin Wall came down and there was no more Cold War. I had gone back to the Navy in ’86 for the trans­plant cen­ter, which nev­er hap­pened, so then I had to work in the lab full time. But in the Navy, all the re­search has to be about com­bat and ca­su­al­ty. They care about HIV, so my first pa­pers were on malar­ia and in­fec­tious dis­ease. And the first CAR-T tri­als were on HIV in the mid-90s.

David Porter

In ’96, my wife got di­ag­nosed with ovar­i­an can­cer and she was in re­mis­sion for 3-4 years. I moved to the Uni­ver­si­ty of Penn­syl­va­nia in 1999 and start­ed work­ing on can­cer be­cause I wasn’t al­lowed to do that with the Navy. My wife was ob­vi­ous­ly a lot of mo­ti­va­tion to do that. She passed away in 2001. Then I start­ed work­ing with David Porter on adop­tive trans­fer T cells.

I got my first grant to do CAR-T cells on HIV in 2004, and I learned a whole lot. I was lucky to have worked on HIV be­cause we did the first tri­als us­ing lentivirus­es, which is an en­gi­neered HIV virus.

I was trained in on­col­o­gy, and then be­cause of the Navy forced to work on HIV. It was ac­tu­al­ly a bless­ing in dis­guise.

So if you hadn’t been draft­ed, you would’ve be­come an en­gi­neer?

Yes. That’s what I was ful­ly in­tend­ing. My dad was a chem­i­cal en­gi­neer, my broth­er is an en­gi­neer. That’s what I thought I was go­ing to do. No one in my fam­i­ly was ever a physi­cian. It’s one of those many quirks of fate.

Back then, we didn’t have these ap­ti­tude tests. It was just hap­haz­ard. I ap­plied to three schools — Berke­ley, Stan­ford and Cal­tech — and I got in­to all three. It was just luck, fate.

And it turned out when I went to the Naval Acad­e­my, they had added a pre-med thing on­to the cur­ricu­lum the year be­fore, so that’s what I did when I start­ed, I did chem­istry.

I would’ve [oth­er­wise] been in nu­clear sub­marines. The most in­ter­est­ing thing in the Navy then was the nu­clear sub tech­nol­o­gy.

You talked about do­ing the first CAR-T tri­als on HIV pa­tients be­cause that’s where the fund­ing was. Was it al­ways in your head that this was even­tu­al­ly go­ing to be some­thing for can­cer?

So I got out of the Navy in ’99 and moved to Penn. I start­ed in ’98 work­ing on treat­ing leukemia, and then once I got to Penn, I con­tin­ued work­ing one day a week on HIV.

It’s kind of a Back-to-the-Fu­ture thing be­cause now can­cer has paved out a path to show that CAR–T cells can work and put down the man­u­fac­tur­ing and it’s go­ing to be a lot cheap­er mak­ing it for HIV. I still think that’s go­ing to hap­pen.

Jim Ri­ley, who used to be a post­doc in my lab, has some spec­tac­u­lar re­sults in mon­keys with HIV mod­els. They have a large NIH and NI­AID re­search pro­gram.

So we’re go­ing to see more and more of that. The CAR tech­nol­o­gy is go­ing to move out­side of can­cer, and in­to au­toim­mune and chron­ic in­fec­tions.

I want to jump over to cy­to­tox­ic re­lease syn­drome (CRS) be­cause a big part of the CRISPR study was that it didn’t pro­voke this po­ten­tial­ly dead­ly ad­verse ef­fect. When did you first be­come aware that CRS was go­ing to be a prob­lem?

I mean we saw it in the very first pa­tient we treat­ed but in all hon­esty, we missed it. I’m an MD, but I don’t see the pa­tient and David Porter took care of the first three pa­tients and our first pe­di­atric pa­tient, Emi­ly White­head.

In our first pa­tients, 2 out of 3, had com­plete re­mis­sion and there were fevers and it was CRS but we thought it was just an in­fec­tion, and we treat­ed with an­tibi­otics for 3 weeks and [even­tu­al­ly] it went away. And sort of mirac­u­lous­ly he was in re­mis­sion and is still in re­mis­sion, 9 years lat­er.

And then when we treat­ed Emi­ly. She was at a 106-de­gree fever over three days, and there was no in­fec­tion.

Tadamit­su Kishi­mo­to

I’ve told this sto­ry be­fore. My daugh­ter has rheuma­toid arthri­tis, and I had been pres­i­dent of the Clin­i­cal Im­mu­nol­o­gists So­ci­ety from 2009 to 2010, and the first good drug for ju­ve­nile rheuma­toid arthri­tis that came out. I was in­vit­ed to give the Japan­ese sci­en­tist Tadamit­su Kishi­mo­to the pres­i­den­tial award for in­vent­ing the drug.

Then in 2012, Emi­ly White­head was lit­er­al­ly dy­ing from CRS, she had mul­ti­ple or­gan fail­ures. And her labs came back and IL-6 lev­els were 1000x nor­mal. It turns out the drug I was look­ing at for my daugh­ter, it blocks IL-6 lev­els. I called the physi­cian and I said, ‘lis­ten there’s some­thing ac­tion­able here, since it’s in your for­mu­la­ry to give it to her off-la­bel.’

And she gave her the ap­pro­pri­ate dose for rheuma­toid arthri­tis. It was mirac­u­lous. She woke up very rapid­ly.

Now it’s co-la­beled. When the FDA ap­proved Kym­ri­ah, it was co-la­beled. It kind of saved the field.

How were you feel­ing dur­ing this time? Did you have any idea what was hap­pen­ing to her?

No, not un­til we got the cy­tokine lev­els, and then it was re­al­ly clear. The cy­tokine lev­els go up and it ex­act­ly co­in­cid­ed. Then we retroac­tive­ly checked out adults and they had ad­verse re­ac­tions and it easy to see. We hadn’t been on the look­out be­cause it wasn’t in our mouse mod­els.

And it ap­peared with those who got cured. It’s one of the first on-tar­get tox­i­c­i­ties seen in can­cer, a tox­i­c­i­ty that hap­pens when you get bet­ter. All the tox­i­c­i­ties from chemother­a­py are off-tar­get: like leukope­nia or hair loss.

I had a physi­cian who had a fever of 106,  I saw him on a fever when he was start­ing to get CRS. When the nurse came in and it said 106, they thought the ther­mome­ter must be bro­ken. On Mon­day, I saw him, and said “how are you feel­ing” and he said “fine.” And I looked at the ther­mome­ter and his tem­per­a­ture was still 102.

Peo­ple will will­ing­ly tol­er­ate on-tar­get tox­i­c­i­ty — that’s very dif­fer­ent from chemother­a­py — if they know it helps get them bet­ter. That’s a new prin­ci­ple in can­cer ther­a­py.

You had these ear­ly CAR–T re­sults al­most at the same time that Doud­na pub­lish­es the first CRISPR pa­pers, then still in bac­te­ria. When did you first start think­ing about com­bin­ing the two?

Yeah, it was pub­lished in Sci­ence in 2012 and that’s when Emi­ly White­head got treat­ed. It’s an amaz­ing thing.

That’s some­thing so or­thog­o­nal. You think ‘how in the heck can that ever ben­e­fit CAR–T cells?׳ but my lab had done the first edit­ed cells in pa­tients, pub­lished in 2012. And we used zinc-fin­gered nu­cle­as­es, which were the pre­de­ces­sors to CRISPR. It knocked out one gene at a time, but we showed it was safe.

I was al­ready in­to gene edit­ing be­cause it could make T cells re­sis­tant to HIV. So it was pret­ty ob­vi­ous that there were can­di­dates in T cells that you can knock out. And al­most every lab start­ed work­ing on some with CRISPR, cause it was much eas­i­er.

We were the first to get full ap­proval by the FDA, so we worked on it from 2012, had all the pre­clin­i­cal da­ta by 2016, and then it takes a while to de­vel­op a lot of new as­says for this as we were very cau­tious to op­ti­mize safe­ty and it took longer than we want­ed, but in the end, we learned a tremen­dous amount.

So what did we learn?

First of all our pa­tients had ad­vanced metasta­t­ic can­cer and had had a lot of chemother­a­py. The first pa­tient had had 3 bone mar­row trans­plants.

One thing is fea­si­bil­i­ty: could you re­al­ly do all the com­plex en­gi­neer­ing? So we found out we could. fea­si­bil­i­ty was passed.

An­oth­er was the fact that cas9 came out of bac­te­ria, forms of strep and staph. Every­one has pre-ex­ist­ing im­mu­ni­ty to Cas9 and we had ex­pe­ri­ence from the first tri­al with Sang­amo [with zinc-fin­ger nu­cle­as­es] where some pa­tients had a very high fever. In that case, we had used ade­n­ovirus­es, and it turned out our pa­tients had very high lev­els of base­line im­mune re­sponse to ade­n­ovirus­es, so we were wor­ried that would hap­pen with CRISPR, and it did not hap­pen.

It did not have any tox­i­c­i­ty. If it had, it would have re­al­ly set the field back. If there was an im­mune re­sponse to cas9 and CRISPR, there could’ve been a re­al bar­ri­er to the field.

And then, the cells sur­vived in the pa­tients. The fur­thest on, it was 9 months. The cells had a very high lev­el of sur­vival. In the pre­vi­ous tri­als, the cells sur­vived less than 7 days. In our case, the half-life was 85 days. We don’t know the mech­a­nism yet.

And we found very big pre­ci­sion in the mol­e­c­u­lar scis­sors, and that was a good thing for the field. You could cut 3 dif­fer­ent genes on 3 dif­fer­ent chro­mo­somes and have such high fi­deli­ty.

It [CRISPR] is liv­ing up to the hype. It’s go­ing to fix all these dis­eases.

What’s the po­ten­tial in CAR-T, specif­i­cal­ly?

Well there’s many many genes that you can add. There are many genes that knock­ing out will make the cells work bet­ter. We start­ed with the cell re­cep­tor. There are many, I think, aca­d­e­mics and biotechs do­ing this now and it should make the cells more po­tent and less tox­ic.

And more broad­ly, what else are you look­ing at for the fu­ture of CAR–T? The week be­fore your pa­per, there were the re­sults from MD An­der­son on nat­ur­al killer cells. 

Dif­fer­ent cell types, nat­ur­al killer cells, stem cells — putting CAR mol­e­cules in­to stem cells, macrophages. One of my grad­u­ate stu­dents start­ed a com­pa­ny to do CAR macrophages and macrophages ac­tu­al­ly eat tu­mor cells, as op­posed to T cells that punch holes in them.

There will be dif­fer­ent cell types and there will be many more ways to ed­it cells. The prime edit­ing and base edit­ing. All dif­fer­ent new vari­a­tions.

You’ve talked about how peo­ple used to think the im­muno-on­col­o­gy, if it ever worked, would nev­er­the­less be a bou­tique treat­ment. De­spite all the ad­vance­ments, No­var­tis and Gilead still have not met the sales they once hoped to grab from their CAR–T treat­ments. Are you con­fi­dent CAR–T will ever be wide­ly ac­ces­si­ble?

Oh yeah, No­var­tis’ sales are go­ing up. They had a hic­cup launch­ing.

Back in ’96 or ’97, when Genen­tech launched Her­ceptin, their com­mer­cial an­ti­body, they couldn’t meet the de­mand ei­ther and then they scaled up and learned how to do bet­ter cul­tures. So right now No­var­tis is us­ing tech in­vent­ed in my lab in the 1990s cul­ture tech that’s com­plex and re­quires a lot of la­bor, so the most ex­pen­sive part is hu­man la­bor. A lot can be made ro­bot­ic. The scale prob­lem will be much eas­i­er.

That’s an en­gi­neer­ing prob­lem that will be­come a thing of the past. The man­u­fac­tur­ing prob­lem will get a lot cheap­er. Here in the US, we have a huge prob­lem with how drugs are priced. We have a prob­lem with pric­ing. That’s a po­lit­i­cal is­sue.

But in cell ther­a­py, it’s just kind of the growth things you see in a new in­dus­try. It’ll get worked out.

This ar­ti­cle has been up­dat­ed to re­flect that Jim Ri­ley con­duct­ed work on CAR in HIV.  

Up­dat­ed: FDA re­mains silent on or­phan drug ex­clu­siv­i­ty af­ter last year's court loss

Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

Big week for Alzheimer’s da­ta; As­traZeneca buys cell ther­a­py start­up; Dig­i­tal ther­a­peu­tics hits a pay­er wall; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

You may start to notice more stories exclusively available to Premium subscribers. This week alone, paid subscribers can read our in-depth reporting on Alzheimer’s data, digital therapeutics and Allogene’s cell therapy for solid tumors, as well as scoops on Twitter ads and Catalent. With your support, we can keep growing our team and spend more time on quality work. We have both individual and company plans available — check them out to unlock the full Endpoints experience.

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Am­gen, years be­hind ri­vals, says PhI obe­si­ty drug shows dura­bil­i­ty signs

While NBC ran “The Biggest Loser” for 17 seasons, deemed toxic by critics for the reality show’s punishing exercise and diet upheavals, researchers in pharmaceutical labs have been attempting to create prescription drugs that induce weight loss — and one pharma betting it can require less frequent dosing is out with a new crop of data.

Amgen was relatively late to the game compared to its approved competitor Novo Nordisk and green light-approaching rival Eli Lilly. But early data suggested Amgen’s AMG 133 led to a 14.5% weight reduction in the first few months of dosing, buoying shares earlier this fall, and now the California pharma is out with its first batch of durability data showing that figure fell slightly to 11.2% about 150 days after the last dose. Amgen presented at the 20th World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease on Saturday afternoon.

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Illustration: Assistant Editor Kathy Wong for Endpoints News

As mon­ey pours in­to dig­i­tal ther­a­peu­tics, in­sur­ance cov­er­age crawls



Talk therapy didn’t help Lily with attention deficit hyperactivity disorder, or ADHD. But a video game did.

As the 10-year-old zooms through icy waters and targets flying creatures on the snow-capped planet Frigidus, she builds attention skills, thanks to Akili Interactive Labs’ video game EndeavorRx. She’s now less anxious and scattered, allowing her to stay on a low dose of ADHD medication, according to her mom Violet Vu.

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Eli Lil­ly’s Alzheimer’s drug clears more amy­loid ear­ly than Aduhelm in first-ever head-to-head. Will it mat­ter?

Ahead of the FDA’s decision on Eli Lilly’s Alzheimer’s drug donanemab in February, the Big Pharma is dropping a first cut of data from one of the more interesting trials — but less important in a regulatory sense — at an Alzheimer’s conference in San Francisco.

In the unblinded 148-person study, Eli Lilly pitted its drug against Aduhelm, Biogen’s drug that won FDA approval but lost Medicare coverage outside of clinical trials. Notably, the study didn’t look at clinical outcomes, but rather the clearance of amyloid, a protein whose buildup is associated with Alzheimer’s disease, in the brain.

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US month­ly costs for biosim­i­lars 'sub­stan­tial­ly high­er' than Ger­many or Switzer­land, JA­MA re­search finds

As the global biologics market is expected to hit nearly the half-trillion-dollar mark this year, new JAMA research points to the importance of timely biosimilar entry, particularly as fewer biosimilars are entering the US than in Europe, and as monthly treatment costs for biosimilars were “substantially higher” in the US compared with Germany and Switzerland.

Among the three countries, biosimilar market share at launch was highest in Germany, but increased at the fastest rate in the US, the authors from the University of Zurich’s Institute of Law wrote in JAMA Network Open today.

Kirk Myers is shown in a still image from a new film series showcasing the efforts of HIV advocates funded by Gilead.

Gilead spot­lights HIV projects and the com­mu­ni­ty lead­ers dri­ving them in new mi­ni-doc­u­men­tary films

Gilead is going behind the scenes of some of the HIV initiatives it funds through grants in a new film series narrated by the people helming the projects.

The first four films and leaders come from across the US — Arianna Lint in Florida and Puerto Rico, Cleve Jones in San Francisco, June Gipson in Mississippi and Kirk Myers in Texas. Their HIV-focused efforts range from addressing unmet needs of the transgender community to delivering social services and high-quality health care in underserved communities.

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EMA pulls an opi­oid from the 1950s used to treat dry cough

The European Medicines Agency said Friday that it’s pulling from all European markets pholcodine-containing medicines, which are an opioid used in adults and children for the treatment of dry cough and in combo with other drugs as a treatment for cold and flu.

The decision to pull the medicines comes as the EMA points to the results from the recent ALPHO study, which show that use of pholcodine during the 12 months preceding anesthesia is linked to a risk of an anaphylactic reaction related to the neuromuscular blocking agents (NMBAs) used (with an adjusted OR of 4.2, and a 95% confidence interval of 2.5 to 6.9).

David Arthur, Salarius Pharmaceuticals CEO

Salarius Phar­ma­ceu­ti­cals sees with­drawals, 3 of 13 pa­tient re­spon­ders in sar­co­ma tri­al

The Houston-based biotech Salarius Pharmaceuticals is lifting the cover on data from a Phase I/II trial for a drug currently on voluntary hold after a patient death, and the results appear to have underwhelmed investors.

Salarius’ candidate, dubbed seclidemstat, is an oral LSD1 inhibitor that is meant to treat Ewing sarcoma and FET-rearranged sarcomas in patients under 12 years old. The biotech had presented data with 13 patients with “first- and second-relapse Ewing sarcoma” who were treated in combination with topotecan and cyclophosphamide.